Hepatocellular carcinoma (HCC) as it is the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide because late detection and high frequency of tumor recurrence render current HCC therapy ineffective. Therefore, increased insight and the development of new therapies are needed. The majority of HCC develops in the background of cirrhosis, a consequence of chronic liver disease characterized by regenerative nodules surrounded by fibrotic scars. This chronic damage to the liver causes proliferation to occur from a progenitor cell compartment because of extensive damage to the mature hepatocytes. Tumor development from progenitor cells is not well understood at this time, yet it is thought that pathways important in both development (Hedgehog, Notch, Wnt) and classic oncogenic pathways (Myc, Ras) are likely involved. At this time, it has been shown that deletion of FoxMlb, a proliferation specific transcription factor, is sufficient to cause growth arrest and apoptosis in hepatocellular carcinoma initiated by a chemical carcinogenesis protocol. FoxMlb is a direct transcriptional target of the Hedgehog signaling factor Gli1, a putative target of the Myc pathway, and the Ras-MAPK pathway is required for FoxM1 activation. Therefore, our primary objective is to examine the relationship between FoxMlb and oncogenic pathways in the turmorigenesis and progression of HCC that has developed from hepatic progenitor cells. Our studies will include harvesting hepatoblasts from a transgenic mouse that is p53 -/- and has the FoxM1 gene flanked by lox sites as well as an Mx-Cre gene, this will allow conditional deletion of FoxM1. Hepatoblasts will be transformed with viral constructs and then introduced into the liver of wildtype animals by intrasplenic injection. In Aim 1, we propose to determine if FoxMlb is needed to initiate tumor development by hepatic progenitor cells that have been transformed with Ras-Myc, Myc, or Smoothened in a p53 null background. In Aim 2, we will determine if conditional deletion of FoxM1 in HCC induced by transformed hepatic progenitor cells leads to growth arrest and apoptosis in tumor cells. Finally, in Aim 3, we will determine if the transcription factor FoxM1 is essential for the expression of proliferation and survival genes, several of which are dysregulated in human HCC (Skp2, Cks1, CENPA, CENPB, Aurora B Kinase, CDC25B, E-Cadherin, p27, Cyclin D1, and Survivin). Completion of these studies will provide insight into the interaction of pathways and factors known to be involved in HCC. In addition, these results could aid in future translational research by identifying patients genetically that will benefit from treatment aimed at decreasing FoxM1 levels, potentially, the treatment of human HCC with an ARF peptide inhibitor.